A Facile Cu(I)/TF-BiphamPhos-catalyzed asymmetric approach to unnatural α-amino acid derivatives containing gem-bisphosphonates

Article abstract of DOI:10.1021/ja2043563

A novel catalytic asymmetric Michael addition of azomethine ylide with β-substituted alkylidene bisphosphates was realized in the presence of a chiral copper(I)/TF-BiphamPhos complex. The present system provides a unique and facile access to enantioenriched unnatural α-amino acid derivatives containing gem-bisphosphonates (gem-BPs) in high yields with excellent diastereoselectivities and enantioselectivities. Subsequent transformations lead to the expedient preparation of biologically active unnatural α-amino acid derivatives containing BPs and bisphosphonic acids without loss of diastereo- and enantiomeric excess.

Full text of DOI:10.1021/ja2043563

ARTICLE
pubs.acs.org/JACS
A Facile Cu(I)/TF-BiphamPhos-Catalyzed Asymmetric Approach
to Unnatural r-Amino Acid Derivatives Containing
gem-Bisphosphonates
Zhi-Yong Xue,† Qing-Hua Li,† Hai-Yan Tao,† and Chun-Jiang Wang*,†,‡
†College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China
‡State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
S Supporting Information
b
ABSTRACT: A novel catalytic asymmetric Michael addition of
azomethine ylide with β-substituted alkylidene bisphosphates
was realized in the presence of a chiral copper(I)/TF-Bipham-
Phos complex. The present system provides a unique and facile
access to enantioenriched unnatural R-amino acid derivatives
containing gem-bisphosphonates (gem-BPs) in high yields with
excellent diastereoselectivities and enantioselectivities. Subse-
quent transformations lead to the expedient preparation of
biologically active unnatural R-amino acid derivatives contain-
ing BPs and bisphosphonic acids without loss of diastereo- and
enantiomeric excess.
’ INTRODUCTION
4,4-Bisphosphono-2-(polyhydroxyl-1,2-dihydro-1,2-methano-
fullerene[60]-61-carboxamido)butyric acid [C60(OH)16AMBP], a
tissue-vectored bisphosphonate fullerene, confers to bone a
stronger affinity for the calcium phosphate mineral hydroxyapa-
tite and hence reduces hydroxyapatite mineralization more
efficiently than C60(OH)30, which does not contain bispho-
sphonic acid groups.10
Because of the important biological activities and potentially
valuable pharmaceutical properties, synthetic methods for gem-
BPs have been intensively investigated in the past decades.
Michael addition of nucleophiles to electron-deficient and highly
reactive tetraethyl vinylidenebis(phosphonate) has been estab-
lished as one of the most efficient approaches for accessing gem-
BPs.11 Despite the large body of catalytic asymmetric Michael
addition reactions in organic synthesis,12 tetraethyl alkylidenebis-
(phosphonate) compounds are underestimated as valuable part-
ners in these reactions, and the limited catalytic asymmetric
Michael additions reported for the synthesis of optically active
gem-BPs containing one formed stereogenic center rely on the
use of less sterically hindered and β-unsubstituted tetraethyl
vinylidenebis(phosphonate) as the Michael acceptor (Scheme 1
left).13
Optically active nonproteinogenic R-amino acids are useful
compounds of great interest and frequently constitute cores of
pharmaceutical agents and biologically active compounds.1 With
the rapid development of protein engineering and the discovery
of peptide-based drugs, the rational design of nonproteinogenic
R-amino acids has attracted considerable attention over the past
decades because of their implementation into nonscissile peptide
mimics and peptide isosteres.2 In addition to bioresolution
procedures,3 Ru- and Rh-catalyzed hydrogenation is broadly
useful for the asymmetric synthesis of many classes of R-amino
acids.4 The asymmetric Strecker reaction,5 asymmetric transi-
tion-metal-mediated additions of various nucleophiles to R-
imino esters,6 and asymmetric alkylation of benzophenone Schiff
base glycine esters using phase-transfer catalysts (PTCs)7 also
provide direct approaches to such compounds and have shown
much promise. Despite fruitful growth in this field, the develop-
ment of more efficient and practical methods for convenient
construction of various nonproteinogenic R-amino acids is still
challenging and in great demand. Geminal bisphosphonates
(gem-BPs), which contain a PꢀCꢀP moiety, are stable pyropho-
sphate analogues and constitute an important class of bioactive
compounds that has been used for the prevention and treatment
of several bone disorders, such as Paget’s disease, bone metas-
tasis, myeloma, osteoporosis, and rheumatoid arthritis.8 Unna-
tural R-amino acid derivatives containing gem-BPs play a
significant role in the study of the structureꢀactivity relationship
of antineoplastic agents, as exemplified in Figure 1. For example,
it has been revealed that the methotrexate (MTX)ꢀBP con-
jugates possess over 5 times greater antineoplastic activity against
osteosarcoma in experimental animal models than MTX alone.9
In sharp contrast, tetraethyl alkylidenebis(phosphonate) com-
pounds with β-substituted groups have not been exploited as
acceptors in the catalytic asymmetric Michael addition. In view of
the simultaneous creation of two adjacent tertiary stereogenic
centers, it is a great challenge to obtain both high enantioselecti-
vity and high diastereoselectivity in asymmetric Michael additions
Received: May 12, 2011
Published: June 27, 2011
r
2011 American Chemical Society
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Figure 1. Examples of biologically important molecules containing gem-BPs.
Scheme 1. Catalytic Asymmetric Michael Addition for the Synthesis of Optically Active gem-BPs Containing One Stereogenic
Center (Previous Work) or Two Adjacent Stereogenic Centers (This Work)
Scheme 2. Proposed Asymmetric Michael Addition for the
Construction of Unnatural r-Amino Acid Derivatives
Containing the gem-BP Motif
involving β-substituted tetraethyl vinylidenebis(phosphonate)
compounds. Herein we describe the first catalytic asymmetric
Michael additions of glycine imino esters7a,e,14 to various β-
substituted tetraethyl alkylidenebis(phosphonate) compounds
using the Cu(I)/TF-BiphamPhos complex,15 which provide
unnatural R-amino acid derivatives containing gem-BPs in good
yields with excellent diastereoselectivity and enantioselectivity
(Scheme 1 right).
’ RESULTS AND DISCUSSION
This work was inspired by our recent finding that the reaction
of alkylidenemalonates with azomethine ylides in the presence of
Ag(I)/TF-BiphamPhos gives 1,3-dipolar cycloadducts15d rather
than Michael adducts, although the latter are the common
products of most asymmetric reactions involving alkylidenema-
lonates (Scheme 2).16 We envisioned that introducing bulkier BP
groups next to the corresponding alkylidene moiety would
efficiently suppress the cycloaddition route, which would be
disfavored because of steric hindrance, and hence facilitate the
formation of unnatural R-amino acid derivatives containing gem-
BPs via Michael addition.
To test this idea, we first examined and compared the
reactivities of methyl cinnamylate (3), diethyl benzylidenemalo-
nate (4), 2-(diethoxyphosphoryl)-3-phenylacrylic acid ethyl es-
ter (5), tetraethyl benzylidenebis(phosphonate) (6a), and
diethyl benzylidenephosphonate (7) with N-benzylidene glycine
methyl ester (2a) under the previously reported15d optimal
reaction conditions for asymmetric 1,3-dipolar cycloaddition
(1,3-DC) of alkylidenemalonates, except that rac-(()-TF-Bi-
phamPhos (1a) was used as the ligand (Scheme 3). The 1,3-
DC pathway occurred exclusively with monoactivated 3 and
bisactivated 4, leading to excellent diastereoselectivity. Replacing
one of the less bulky ethoxycarbonyl groups in 4 with a much
bulkier P(O)(OEt)2 group in 5 still gave rise to cycloadducts
10 and 11, albeit with low diastereoselectivity. However, the
1,3-DC pathway was suppressed and the Michael addition
(MA) pathway occurred with excellent diastereoselectivity
(>99:1) when both of the less bulky CO2Et groups in 4 were
replaced with the bulkier P(O)(OEt)2 groups in 6a. On the
contrary, no reaction occurred with the corresponding mono-
activated phosphonate 7 under the same reaction conditions,
which indicates that two bulkier phosphonate groups on the
β-substituted olefin (6a) are required for this transition-
metal-catalyzed Michael addition reaction to occur. The vinyl-
phosphonate showed much lower reactivity, a finding also
noticed by Alexakis and co-workers13a,b in the organocatalyzed
asymmetric Michael addition of aldehyde to β-unsubstituted
vinylphosphonates.
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Scheme 3. Reaction Pathway and Reactivity Studies of β-Substituted Vinylcarboxylate 3, β-Substituted Vinylidenebis-
(carboxylate) 4, β-Substituted Vinylidenecarboxylateꢀphosphonate 5, β-Substituted Vinylidenebis(phosphonate) 6a, and
β-Substituted Vinylphosphonate 7
Asymmetric Michael Addition To Construct the Optially
Active gem-BP Motif. Having established the substrate-con-
trolled Michael addition reaction pathway exerted by the gem-BP
group on the β-substituted olefin, we then conducted the novel
asymmetric reaction to evaluate the enantioselectivity with chiral
TF-BiphamPhos ligand. To our delight, the reaction of tetraethyl
benzylidenebis(phosphonate) 6a with N-benzylidene glycine
methyl ester 2a catalyzed by Ag(I)/(S)-TF-BiphamPhos [(S)-
1a] indeed gave the desired Michael adduct 12 in 82% yield with
remarkable diastereoselectivity (99:1) and 30% enantioselectiv-
ity within 3 h at room temperature.17 Encouraged by this positive
result, we screened various metal salts to examine the effect of
different Lewis acids. Representative results are summarized in
Table 1. Though gold(I) proved to be inactive in this transfor-
mation (Table 1, entry 2), Cu(CH3CN)4BF4 combined with
ligand (S)-1a showed high reactivity and better enantioselec-
tivity: the reaction was finished within less than 15 min, affording
the desired sole adduct in 95% yield with 77% ee (entry 3).
Subsequent ligand screening revealed that TF-BiphamPhos 1e
bearing bromines at the 3 and 30 positions of the TF-BIPHAM
backbone was the most effective chiral ligand, providing 12 as the
sole product in high yield and 84% ee (entry 7; see the
Supporting Information for more details). The choice of solvent
was also important: CH2Cl2 and CHCl3 were identified as the
most suitable solvents (entries 7 and 13). The effect of the ratio
of chiral ligand to Cu(CH3CN)4BF4 on the enantioselectivity
was also examined. The catalysts prepared from Cu(CH3CN)4BF4
and 1e in 1:1 and 1:2 ratios showed similar results for the yields
and enantioselectivities (entries 7 and 14). Reducing the tem-
perature to ꢀ20 °C in CH2Cl2 led to completion of the reaction
with 94% ee in less than 30 min (entry 15). Access to both
enantiomers was found to be possible with the same level of
enantioselectivity (entries 15 and 16). The catalyst loading was
successfully reduced to 1 mol % without any loss of reactivity or
enantioselectivity (entry 17). Even when the catalyst loading was
reduced to 0.1 mol %, comparable results (57% yield and 94% ee)
were still achieved with extended reaction time (entry 18).
Since the acidity of the C(R)ꢀH bond in the glycine imino
ester is affected by a resonance-assisted hydrogen bond,18 the
electronic and steric properties of the glycine imino ester were
tuned for further optimization, and the results are summarized in
Table 2. To simplify the determination of the enantiomeric
excess, different Michael adducts with respect to the Schiff base
moiety could be easily transferred into the deprotected product
13a19 and then analyzed under the same HPLC separation
conditions. Generally, aromatic aldehyde-derived imino esters
gave higher enantioselectivities and reactivities than aliphatic
ones (Table 2, entries 1ꢀ8), and the latter afforded only trace
amounts of product even at room temperature after 48 h (entry
9). The electronic property of the substituent on the aryl ring has
significant effect on this transformation: an electron-deficient
substituent at the para position of the phenyl ring led to the same
selectivity and reactivity as the model substrate (entries 2 and 3),
whereas an ortho substituent had a negative effect on the
enantioselectivity, probably caused by the disfavored steric
congestion (entries 6 and 7). In contrast, electron-rich aromatic
aldehyde derivatives displayed remarkably decreased reactivity,
especially the p-methoxybenzaldehyde derivative, for which a
yield of only 46% was achieved in 48 h at ꢀ20 °C, although the
enantioselectivity was kept at the same level (entry 5). Benzo-
phenone Schiff base could not be employed in this transforma-
tion (entry 10), probably because of the reduced acidity of the
C(R)ꢀH bond in the corresponding imino ester.20 The different
reactivities and stereoselectivities of those glycine imino esters
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Table 1. Screening Studies of the Asymmetric Michael Addition of Imino Ester 2a and Tetraethyl Benzylidenebis-
(phosphonate) 6aa
entry
TF-BiphamPhosb
[M]
solvent
T (°C)
time (min)
yield (%)c
ee (%)d
1
2
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(S)-1e
(R)-1e
(R)-1e
AgOAc
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
rt
180
180
15
82
ꢀ
30
ꢀ
Au(c-HexNC)2BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
Cu(CH3CN)4BF4
rt
3
rt
95
87
75
86
90
83
85
87
86
85
84
86
92
90
91
57
77
8
4
rt
300
300
300
15
5
rt
10
32
84
57
63
53
64
72
84
84
94
95
94
94
6
rt
7
rt
8
rt
180
90
9
THF
rt
10
11
12
13
14e
15
16
17f
18g
hexene
EtOAc
acetone
CHCl3
CHCl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
120
180
180
15
rt
rt
rt
rt
15
ꢀ20
ꢀ20
ꢀ20
ꢀ20
30
30
30
2880
a All of the reactions were carried out with 0.23 mmol of 6a and 0.35 mmol of 2a in 2 mL of solvent. b Structures of the ligands are shown below. c Isolated
yields. d Determined by HPLC analysis. e CuBF4 (3 mol %) and (R)-1e (6 mol %). f Run with 1 mol % catalyst. g Run with 0.1 mol % catalyst.
indicate that this Michael addition was affected not only by the
acidity of the C(R)ꢀH bond in the glycine imino ester but also
by the steric hindrance and electronic effect of the imino moiety
in the glycine imino ester. It could not be ascribed to the
reversibility of this asymmetric Michael addition reaction be-
cause a 31P NMR investigation showed that this reaction is not
reversible (see the Supporting Information for details).
Under the optimal reaction conditions, a series of representa-
tive β-substituted alkylidenebis(phosphonate) compounds were
next explored to examine the substrate scope and limitation of
this novel Michael addition. As shown in Table 3, alkylidenebis-
(phosphonate) compounds bearing electron-rich (entries 3ꢀ5),
electron-neutral (entries 1, 2, and 13), or electron-deficient
groups (entries 6ꢀ12) on the aryl rings reacted smoothly with
glycine methyl ester 2a, exclusively affording the corresponding
adducts (13aꢀl) in high yields (85ꢀ95%) with good enantios-
electivities (93ꢀ99%) at ꢀ20 °C within 0.5 h. The substitution
pattern and electronic property of the phenyl ring had little effect
on the enantioselectivity. It is noteworthy that comparable
excellent performance was still achieved for the sterically hin-
dered o-chloro-substituted BP 6f in terms of diastereo- and
enantioselectivity and reactivity (entry 7). Additionally, hetero-
aryl-substituted alkylidenebis(phosphonate) 6m derived from
2-furylaldehyde also worked well in this transformation, leading
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Table 2. Influence of the Imino Ester 2 in the Cu(I)-Catalyzed Asymmetric Michael Addition of Tetraethyl Benzylidenebis-
(phosphonate) 6aa
entry
R1
Ph (2a)
R2
T (°C)
time (min)
yield (%)b
ee (%)c
1
2
H
H
H
H
H
H
H
H
H
Ph
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
rt
30
30
90
88
91
88
46
85
89
78
50
ꢀ
94
94
94
92
95
83
84
80
92
ꢀ
p-F-Ph (2b)
p-Br-Ph (2c)
p-Me-Ph (2d)
p-MeO-Ph (2e)
o-Me-Ph (2f)
o-Cl-Ph (2g)
2-naphthyl (2h)
cyclohexyl (2i)
Ph (2j)
3
30
4
30
5
1440
30
6
7
30
8
30
9
2880
30
10
ꢀ20
a All of the reactions were carried out with 0.23 mmol of 6a and 0.35 mmol of 2 in 2 mL of solvent. b Isolated yields. c Determined by HPLC analysis.
Table 3. Substrate Scope of Cu(I)-Catalyzed Asymmetric Michael Additions of Imino Ester 2a and Various β-Substituted
Alkylidenebis(phosphonates) 6a
entry
ligand
R
13
yield (%)b
ee (%)c
1
2
(R)-1e
(S)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
(R)-1e
Ph (6a)
13a
13a
13b
13c
13d
13e
13f
90
85
92
90
95
85
90
88
90
89
88
91
85
82
71
76
73
72
70
75
94
95
99
95
97
95
96
98
99
95
95
93
96
96
95
95
95
89
90
89
Ph (6a)
3
p-Me-Ph (6b)
m-Me-Ph (6c)
p-MeO-Ph (6d)
p-Cl-Ph (6e)
o-Cl-Ph (6f)
m-Cl-Ph (6g)
p-F-Ph (6h)
p-Br-Ph (6i)
p-CF3ꢀPh (6j)
p-NO2ꢀPh (6k)
2-naphthyl (6l)
2-furyl (6m)
Me (6n)
4
5
6
7
8
13g
13h
13i
9
10
11
12
13
14
15
16
17
18
19
20
13j
13k
13l
13m
13n
13o
13p
13q
13r
13s
Et (6o)
Pr (6p)
CyCH2 (6q)
iBu (6r)
H (6s)
a All of the reactions were carried out with 0.23 mmol of 6 and 0.35 mmol of 2a. b Isolated yields of 13aꢀm and the corresponding benzoylated
compounds 13nꢀs using β-aryl-substituted (entries 1ꢀ14) and β-alkyl-substituted (entries 15ꢀ20) alkylidenebis(phosphonate) compoundss,
respectively, as acceptors. c Determined by HPLC analysis.
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to 82% yield and 96% ee (entry 14). Remarkably, the alkyl-
substituted alkylidenebis(phosphonate) compounds derived
from both linear (6nꢀp) and branched (6q and 6r) aliphatic
aldehydes proved to be excellent substrates with respect to
diastereoselectivity and enantioselectivity (entries 15ꢀ19).
The less bulky Michael acceptor tetraethyl vinylidenebis-
(phosphonate) (6s) was also tested in this catalytic system,
and a good yield and ee (89%) were also achieved for the
desired adduct, which contains one newly formed stereogenic
center (entry 20).
the Supporting Information for more details). Those of other
adducts were deduced on the basis of this result.
Reaction Mechanism. In order to gain mechanistic insight
into the nature of the possible active species formed in this highly
efficient catalytic system, the relationship between the ee values
for the Michael adduct and the ee values for the chiral ligand was
also examined. As shown in Figure 3, with TF-BiphamPhos (S)-
1e as the chiral ligand, we observed a clear linear effect in the
asymmetric Michael addition of 2a to 6a. Such a linear correla-
tion between the product ee and the ligand ee indicates that the
possible active species in this highly efficient Cu(I)/TF-Bipham-
Phos-catalyzed Michael addition reaction is a monomeric Cu(I)
complex having (S)-TF-BiphamPhos as a bidentate chiral ligand
[Cu(I):1e = 1:1].21
The relative and absolute configuration of 13a produced using
CuBF4/(R)-TF-BiphamPhos [(R)-1e] was unequivocally deter-
mined to be (2S,3R) by X-ray diffraction analysis (Figure 2; see
The significant role played by the amino group of the chiral
TF-BiphamPhos ligand in this catalytic system was further
demonstrated through a control experiment using the chiral
ligand (R)-1f, in which the amino group connected to the upper
aryl ring had been removed according to the synthetic route
from the chiral backbone (S)-TF-BIPHAM22 in four steps
(Scheme 4). Under the optimized reaction conditions but with
(R)-1f as the ligand, the Michael addition of 2a to 6a became very
sluggish, and the corresponding Michael adduct 12 was formed
in 85% yield with only 7% ee even after 24 h, although the
diastereoselectivity was still kept at the same high level. This
indicates that the NH2 moiety of the chiral TF-BiphamPhos
indeed plays a great role in this asymmetric Michael addition
reaction.
Figure 2. X-ray crystal structure of (2S,3R)-13a.
According to the previous literature, this asymmetric Michael
addition reaction could be explained through the proposed
transition state illustrated in Figure 4. The in situ-formed
azomethine ylide is coordinated to the copper center of the
active species bearing (S)-TF-BiphamPhos as the chiral ligand
and oriented in the favored tetracoordinated transition state23
because of the steric repulsion between the phenyl group in the
ylide and the phenyl ring on the phosphorus atom of the chiral
ligand. The high steric congestion imposed by the latter effec-
tively blocks the approach of 6a from the back side of the
coordinated azomethine ylide, giving instead the Michael adduct
13a in the (2R,3S) configuration through front-side attack.
Therefore, the opposite enantiomer, (2S,3R)-13a, is generated
from the corresponding active Cu(I) species having (R)-TF-
BiphamPhos as the chiral ligand. The phosphonate group of 6a
can coordinate to the Cu(I) center, which can stabilize the
negatively charged oxygen atom in the proposed transition
state.23 We cannot rule out the possible hydrogen-bonding
interaction between the phosphonate group and the NH2 group
of the chiral ligand, which also could facilitate stabilization of the
proposed transition state.24
Figure 3. Linear correlation of the adduct and ligand ee's in the
asymmetric Michael addition of 2a to 6a catalyzed by Cu-
(CH3CN)4BF4/(S)-1e.
Figure 4. Proposed transition state leading to the syn Michael adduct (2R,3S)-13a with the Cu(I)/(S)-1a Complex.
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Scheme 4. Synthesis of Chiral Ligand 1f and Control Experiments To Evaluate the Role of the NH2 Group of the TF-BiphamPhos
Ligand in the Asymmetric Michael Addition Reaction
Scheme 5. Cleavage of the Tetraethyl Group in Michael Adduct 13a for the Synthesis of Bisphosphonic Acid 18
Synthetic Transformation of the Michael Adduct. To
illustrate the utility of this novel Michael addition, transforma-
tions of the optically active adduct 13a containing the gem-BP
group were subsequently investigated. The biologically active
bisphosphonic acid 18, which constitutes a core component of
various biologically active compounds,9,10,25 was easily attained
through cleavage of the tetraethyl group in the BP moiety of 13a
with TMSI26 at room temperature in quantitative yield without
loss of diastereo- and enantiomeric excess, as confirmed by
the fact that the same ee value was measured for tetramethyl
bisphosphonate 19, which was obtained in turn by simultaneous
esterification and methylation of 18 with trimethylsilyl diazo-
methane (Scheme 5).
On the other hand, R-fluorinated and -chlorinated compounds
21 and 22, which are analogues of monohalogenated methyl-
enebis(phosphonate) compounds,27 were easily obtained by
benzoylation and subsequent halogenation via treatment of the
corresponding carbanion of 20 with Selectfluor and N-chloro-
succinimide (NCS), respectively (Scheme 6).26 A hydroxyl group
could be also be directly introduced into the BP moiety, forming
the corresponding optically active R-hydroxybis(phosphonate)
23. This methodology offers a unique and facile access to derivatives
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Scheme 6. r-Fluorinated, -Chlorinated, and -Hydroxylated Bisphosphonate Derivatives of Michael Adduct 13a
of unnatural R-amino acids1 containing gem-BPs and bisphos-
phonic acids,8 which is expected to find valuable applications in
medicinal chemistry.
Excellent Talents in University (NCET-10-0649), and the
Fundamental Research Funds for the Central Universities.
’ REFERENCES
’ CONCLUSION
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(d) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789. (e) Kotha, S. Acc. Chem. Res. 2003,
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In summary, we have successfully developed the first example
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realizing the direct asymmetric Michael addition of azo-
methine ylides to tetraethyl alkylidenebis(phosphonate)
compounds under mild conditions. The highly efficient Cu-
(CH3CN)4BF4/TF-BiphamPhos catalytic system exhibited
excellent performance, providing the nonproteinogenic R-
amino acid derivatives containing gem-BPs in good yields with
excellent diastereoselectivities (>99:1) and high enantios-
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led to the expedient preparation of biologically active BPs and
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’ ASSOCIATED CONTENT
S
Supporting Information. Complete refs 11a and 11c,
b
experimental procedures, compound characterization data, and
crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
cjwang@whu.edu.cn
’ ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (20972117), SRFDP (20090141110042),
the 973 Program (2011CB808600), the Program for Changjiang
Scholars and Innovative Research Team in University of the
Ministry of Education (IRT1030), the Program for New Century
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11764
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